WO2017200318A1 - Use of carbamate compound for preventing or treating fibromyalgia or functional syndrome associated with fibromyalgia - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating fibromyalgia or a functional syndrome associated with fibromyalgia, the pharmaceutical composition comprising: a carbamate compound of chemical formula 1 or a pharmaceutically acceptable salt thereof, a solvate or a hydrate; and a pharmaceutically acceptable carrier. The pharmaceutical composition, according to the present invention, may enable the efficient treatment of fibromyalgia or a functional syndrome associated with fibromyalgia.

Description

Use of carbamate compounds to prevent or treat fibromyalgia or associated functional syndrome of fibromyalgia

The present invention relates to a use for the purpose of preventing or treating fibromyalgia or related functional syndrome of fibromyalgia by administering a pharmaceutical composition comprising a carbamate compound of formula (I):

[Formula 1]

In Chemical Formula 1, R ₁ , R ₂ , A ₁ and A ₂ are as defined herein.

Fibromyalgia, also called fibromyalgia syndrome, is a complex syndrome consisting of pain such as central sensitization, hyperalgesia, and spontaneous pain. Fibromyalgia is a chronic systemic pain disorder that is accompanied by various symptoms such as chronic fatigue, sleep disorders, cognitive disorders, and depression. In particular, it is often accompanied by extensive pain, stiffness and tenderness in musculoskeletal related tissues including muscles, tendons and ligaments (Bennett RM, Clinical manifestations and diagnosis of fibromyalgia, Rheum Dis Clin North Am. , 2009; Clauw DJ, Fibromyalgia and related conditions, Mayo Clin Proc., 2015).

Fibromyalgia has a prevalence of 2 to 8% depending on diagnostic criteria. According to the diagnostic criteria published in 1990, fibromyalgia was diagnosed according to chronic systemic pain and the presence of a certain number of pain points. According to these criteria, the prevalence of fibromyalgia is much higher in women. The criteria proposed in 2010 and 2011 no longer include the number of pain points in the criteria for diagnosing fibromyalgia, and the criteria for diagnosing the symptoms associated with chronic pain such as fatigue, sleep disorders, cognitive impairment and depression The number of male patients diagnosed with fibromyalgia increased, and the ratio of male to female patients changed from 9: 1 in 1990 to 2: 1 in the new standard.

Almost all patients diagnosed with fibromyalgia often experience multiple chronic pains in different parts of the body during their lifetime, and pain experiences in different parts of the body eventually progress to chronic systemic pain. Fibromyalgia often begins in childhood or adolescence, and patients diagnosed with fibromyalgia often have headaches, menstrual irregularities, temporomandibular joint disorders, chronic fatigue, inflammatory bowel disease, and other areas. There is a high likelihood of experiencing pain, and these patients do not have successful pain suppression with surgical therapy to remove partial pain. Fibromyalgia is a typical centralized pain and is a pain situation that is distinct from nociceptive pain and neuropathic pain that can be easily distinguished by a clinician.

Although the pathological mechanism of fibromyalgia is not fully understood to date, several environmental factors are expected to work as well as genetic factors. Families of patients diagnosed with fibromyalgia are 8.5 times more likely to suffer from the same disease than the general population, and according to twin studies, fibromyalgia is caused by 50% genetic factors and 50% environmental factors. It is known to appear by. The main environmental factors that promote fibromyalgia are stress factors of various factors, such as those that cause acute pain for several weeks. The development of fibromyalgia is influenced by a variety of psychological, behavioral, and social factors, and the treatment is complicated by these various pathogenesis factors.

Various pharmacological and non-drug treatments are being performed for the treatment of fibromyalgia. Drugs such as tricyclic compounds, gabapentinoids, and serotonin-norepinephrine reuptake inhibitors are used for pharmacological treatment, but various drugs are used in combination due to the complicated mechanisms of fibromyalgia. to be.

Various drugs are used for the treatment of fibromyalgia, but due to the complications of chronic fatigue, depression, as well as systemic musculoskeletal pain, there are still limitations on the use due to side effects. There is still a need for new drugs with improved efficacy and side effects.

The present invention seeks to provide a method for preventing or treating fibromyalgia or associated functional syndrome of fibromyalgia.

It is also an object of the present invention to provide a use of a carbamate compound of formula (1), or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in the prevention or treatment of fibromyalgia or associated functional syndrome of fibromyalgia :

[Formula 1]

In Chemical Formula 1, R ₁ , R ₂ , A ₁ and A ₂ are as defined herein.

The present invention provides a medicament for the prevention or treatment of fibromyalgia or associated functional syndrome of fibromyalgia, comprising a therapeutically effective amount of a carbamate compound of Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof: :

[Formula 1]

In Chemical Formula 1,

R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, C ₁ -C ₈ alkyl, halo-C ₁ -C ₈ alkyl, C ₁ -C ₈ thioalkoxy and C ₁ -C ₈ alkoxy,

One of A ₁ and A ₂ is CH and the other is N.

In addition, the present invention is a fibromyalgia or fibromyalgia comprising a therapeutically effective amount of the carbamate compound of Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and at least one pharmaceutically acceptable carrier It provides a pharmaceutical composition for the prevention or treatment of the associated functional syndrome of.

In addition, the present invention comprises administering to a subject a therapeutically effective amount of a carbamate compound of Formula 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the associated functional syndrome of fibromyalgia or fibromyalgia in a subject It provides a method of preventing or treating.

The present invention also provides a use of the carbamate compound of Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof for the prevention or treatment of fibromyalgia or associated functional syndrome of fibromyalgia.

According to an embodiment of the present invention, in Formula 1 R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen and C ₁ -C ₈ alkyl.

In one embodiment, halo C ₁ -C ₈ alkyl is perfluoroalkyl.

According to another embodiment of the invention, the carbamate compound of formula 1 is carbamic acid (R) -1- (2-chlorophenyl) -2-tetrazol-2-yl) ethyl ester of formula

[Formula 2]

Preparation of the carbamate compounds of Formulas 1 and 2 can be prepared using those known in the art, or compounds that can be easily prepared from those skilled in the art. In particular, methods for the preparation of compounds of formula 1 are described in detail in International Publication Nos. WO 2006/112685 A1, WO 2010/150946 A1 and WO 2011/046380 A2, which are incorporated herein by reference. The compound of the present invention may be chemically synthesized by the method described in the above document, but this is merely to present one exemplary method, and the order of the unit operation and the like may be selectively changed as necessary. It is not intended to be limiting.

The compound of the present invention can be used for the treatment of fibromyalgia, and fibromyalgia includes fibromyalgia syndrome.

According to one embodiment of the present invention, fibromyalgia is a fibromyalitis, fibromyalitis, myopathy, musculoskeletal pain syndrome, non-articular rheumatoid, rheumatoid myositis pain and tension myalgia, hyperalgesia, persistent pain, stiffness and stiffness and tenderness.

In one embodiment the compounds herein can also be used for the prevention or treatment of associated functional symptoms of fibromyalgia. Associated functional syndromes of fibromyalgia include headache, insomnia, cognitive impairment, depression, body temperature disorders, irritable bowel syndrome, sicca symptoms, increased sweating, dizziness, tremor, dyspnoea, arrhythmias , Paraesthesias and chronic fatigue.

Pain in the musculoskeletal system is a major feature of fibromyalgia, and animal models that are associated with musculoskeletal pain in humans can be used to evaluate the efficacy of a therapeutic agent for treating fibromyalgia. For example, repeated injections of acidic saline into the spleen muscles of rats result in mechanical allodynia due to central mechanisms, which may well represent muscle pain or tenderness observed in patients with fibromyalgia (Sluka KA et. al., Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia, Muscle Nerve. 2001).

Dosages of the compounds for the prevention or treatment of the disease will typically depend on the severity of the disease, the weight of the subject and the metabolic state. By “therapeutically effective amount” for an individual patient is meant the amount of active compound or pharmaceutical agent sufficient to achieve the pharmacological effect, ie, the therapeutic effect, described above. The therapeutically effective amount of the compound of the present invention is preferably 50 to 500 mg, preferably 50 to 400 mg, more preferably 50 to 300 mg, more preferably 50 to 200 mg on a daily administration to a human. .

The compounds of the present invention can be administered by conventional methods used for the administration of therapeutic agents, such as oral, parenteral, intravenous, intramuscular, subcutaneous or rectal administration.

A medicament or pharmaceutical composition according to one embodiment of the invention may comprise a therapeutically effective amount of a compound selected from the group consisting of the compounds herein, pharmaceutically acceptable salts, solvates, hydrates and combinations thereof. .

Pharmaceutically acceptable salts of carbamate compounds of Formula 1 include, for example, independently, acetate, benzenesulfonate, benzoate, bitartrate, calcium acetate, camsylate, carbonate, citrate, edde Tate, Edsylate, Estoleate, Ecylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycoylarsanylate, Hexyl resornate, Hydrabamine, Hydrobromide, Hydrochloride, Hydrogencar Carbonate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylnitrate, methylsulfate, no catenate, lead silicate, nitrate Latex, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturone Yew. Salicylates, stearates, subacetates, succinates or hemi-succinates, sulfates or hemi-sulfates, tannates, tartrates, oxalates or hemi-tartrates, the thiolates, triethiodes , Benzatin, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, ammonium, tetramethylammonium, calcium, lithium, magnesium, potassium, sodium and zinc and the like.

The pharmaceutical or pharmaceutical composition according to one embodiment of the present invention may be administered orally or parenterally, and in the case of parenteral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration Administration, vaginal administration, pulmonary administration, rectal administration, and the like. Upon oral administration, the pharmaceutical compositions according to one embodiment may be formulated to coat the active agent or protect it from degradation in the stomach. In addition, the composition may be administered by any device in which the active substance may migrate to the target cell. The route to be administered may vary depending on the general conditions and age of the subject to be treated, the nature of the treatment condition and the active ingredient selected.

Suitable dosages of the medicament or pharmaceutical composition according to one embodiment of the invention are formulated with the method of administration, mode of administration, age, weight, sex, morbidity, food, time of administration, route of administration, rate of excretion and response of the patient. Depending on the same factors, usually skilled practitioners can easily determine and prescribe a dosage effective for the desired treatment or prophylaxis. The pharmaceutical composition according to one embodiment may be administered in one or several doses, for example, may be administered divided into once to four times a day. The pharmaceutical composition according to one embodiment may include 50 to 500 mg, preferably 50 to 400 mg, more preferably 50 to 300 mg, more preferably 50 to 200 mg of the compound of Formula 1.

The pharmaceutical composition according to one embodiment is a unit dose by formulating with a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by those of ordinary skill in the art It may be made in the form or prepared by incorporation into a multi-dose container. In this case, the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or may be in the form of extracts, powders, granules, tablets or capsules, and may further include a dispersant or stabilizer. In addition, the pharmaceutical composition may be administered in the form of suppositories, sprays, ointments, creams, gels, inhalants or skin patches. The pharmaceutical composition may also be prepared for mammalian administration, more preferably for human administration.

Pharmaceutically acceptable carriers may be solid or liquid, excipients, antioxidants, buffers, bactericides, dispersants, adsorbents, surfactants, binders, preservatives, disintegrants, sweeteners, flavoring agents, glidants, release controlling agents, wetting agents, It may be at least one selected from stabilizers, suspending agents and lubricants. In addition, the pharmaceutically acceptable carrier may be selected from saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and mixtures thereof.

In one embodiment, suitable excipients include sugars (eg dextrose, sucrose, maltose and lactose), starch (eg corn starch), sugar-alcohols (eg mannitol, sorbitol, maltitol, erythritol and Xylitol), starch hydrolysates (such as dextrin and maltodextrin), cellulose or cellulose derivatives (such as microcrystalline cellulose), or mixtures thereof, may be used.

In one embodiment, suitable binders include povidone, copovidone, methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, gums, sucrose, starch or Mixtures thereof may be used, but are not limited thereto.

In one embodiment, suitable preservatives include benzoic acid, sodium benzoate, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorbutol, gallate, hydroxybenzoate, EDTA, or mixtures thereof. May be used, but is not limited thereto.

In one embodiment, as a suitable disintegrant, starch glycolate sodium salt, crosslinked polyvinyl pyrrolidone, crosslinked carboxymethylcellulose, starch, microcrystalline cellulose or mixtures thereof may be used. However, the present invention is not limited thereto.

In one embodiment, suitable sweeteners may include sucralose, saccharin, sodium or potassium or calcium saccharin, acesulfame potassium or sodium cyclamate, mannitol, fructose, sucrose, maltose or mixtures thereof, but It is not limited.

In one embodiment, suitable glidants may include, but are not limited to, silica, colloidal silicon dioxide, talc, and the like.

In one embodiment, suitable lubricants may include, but are not limited to, long chain fatty acids and salts thereof such as magnesium stearate and stearic acid, talc, glyceride wax or mixtures thereof.

As used herein, the term “subject” refers to an animal, preferably a mammal (eg, primates (eg, humans), cattle, sheep, goats, horses, dogs, cats, which are the subjects of prophylaxis or treatment). , Rabbit, rat, mouse, etc.), most preferably human.

As used herein, the terms "prevent", "preventing" and "prevention" are intended to reduce or eliminate the likelihood of disease.

The terms "treat", "treating" and "treatment" as used herein are intended to eliminate all or part of a disease and / or its accompanying symptoms.

Pharmaceuticals and pharmaceutical compositions according to the present invention can effectively prevent or treat fibromyalgia. In addition, the pharmaceutical and pharmaceutical composition according to the present invention can effectively prevent or treat the associated functional syndrome of fibromyalgia.

1 shows carbamic acid (R) -1-prepared in the preparation for the reduction of paw withdrawal threshold (PWT) for paw paw stimulation of rats induced by right spleen muscle administration of acidic saline (pH 4.0) The effect of (2-chlorophenyl) -2-tetrazol-2-yl) ethyl ester (hereinafter referred to as "test compound") is shown.

2 is a graph showing the area under the curve of the paw avoidance threshold curve compared to the vehicle group and the test compound administration group.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are only intended to illustrate one or more embodiments, but the scope of the invention is not limited thereto.

Production Example : Carbamic acid (R) -1- (2- Chlorophenyl )-2- Tetrazole 2-yl) ethyl ester

Carbamic acid (R) -1- (2-chlorophenyl) -2-tetrazol-2-yl) ethyl ester was prepared according to the method described in Preparation 50 of International Publication No. WO 2010/150946.

Example : Fibromyalgia  Experiment of pain suppression effect using animal model

Pain in the musculoskeletal system is the biggest feature of fibromyalgia. A model was developed by Sluka KA for musculoskeletal pain in humans, characterized by hyperalgesia induced by repeated injections of acidic saline intramuscularly.

An experiment evaluating the effects of sustained mechanical allodynia on the muscle pain or tenderness observed in patients with fibromyalgia. Repeated injections of acidic saline into the spleen muscles of rats resulted from mechanical failure due to central mechanisms. Allodynia occurs (Sluka KA et. Al., Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia, Muscle Nerve. 2001).

Laboratory animals

Male rats (Sprague-Dawley, 150-200 g, 6 weeks old, Orient Bio Co., Ltd.) were purchased and acclimated to animal chambers for at least one week. The experimental animals were maintained at a light and dark cycle of 12 hours, a temperature of 22 to 25 ° C., and a relative humidity of 40 to 60%, and water and food were freely accessible.

Mechanical Allodynia  Measure

Mechanical allodynia was assessed by measuring the paw withdrawal threshold of the rat right hind paw using Dixon's 'up-down method' (Chaplan et. Al., Quantitative assessment of tactile). allodynia in the rat paw.J Neurosci Methods, 1994; Dixon WJ, Efficient analysis of experimental observations, Annu Rev Pharmacol Toxicol. 1980). First, the rats were placed in an acrylic box (13 x 25 x 13 cm ³ ) placed on a wire mesh installed about 35 cm from the bottom and allowed to stabilize for 20 minutes or more. Eight von Frey filaments (0.2, 0.4, 0.6, 1.0, 2.0, 4.0, 6.0, 8.0, 15.0 g) with various bending forces were used. Flexural force was applied starting with 2.0 g of filament perpendicular to the plantar surface. When the avoidance reaction was not shown, the next higher bending force filament was applied, or when the avoidance reaction was shown, the next lower bending force filament was applied. Application of the filament was carried out four more times after changing the avoidance reaction to obtain at least six reaction results. Starting at 2.0 g, 0.2 g for the reaction for 4 consecutive filaments and 15.0 g for the 5 consecutive reactions were designated.

Mechanical Allodynia  cause

Rat right hind paw was used to measure baseline avoidance response thresholds for mechanical stimulation. 100 μl of preservative-free acidic saline (0.9% sodium chloride, pH 4.0) was intramuscularly injected into the right sphincter of the rat. After 5 days, acidic saline was intramuscularly injected into the same site using the same method. Seven or eight days after the second acidic saline administration, the incidence of mechanical allodynia was confirmed by measuring the avoidance response threshold for mechanical stimulation on the right hind paw. Rats with a threshold threshold of mechanical avoidance response less than 4.5 g were used for evaluation of the test drug. (Sluka KA et. Al., Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia, Muscle Nerve. 2001).

dosage

Test compounds were prepared as solutions using 30% PEG 400 and 70% distilled water by volume. Each solution was administered intraperitoneally in a volume of 3 ml per kg rat. Evasion thresholds for mechanical stimulation were measured at 30 minutes, 1, 2 and 4 hours of drug administration.

statistics

The effect of the test compound was expressed as mean ± standard error, and analyzed using “one-way ANOVA and Dunnett test” and compared each with “% MPE (percent of best possible effect)”. Statistical significance was recognized when the data differed by p <0.05.

[% MPE = (Threshold over time after drug treatment-threshold at 0 hours) / (Normal threshold-threshold at 0 hours) × 100]

As a result of repeated injections of acidic saline twice, it was confirmed that the avoidance response threshold for mechanical stimulation was significantly reduced compared to the normal group (Table 1 and FIG. 1, the avoidance response threshold at 0 hours of the normal group and the acidic saline administration group). Comparison), which is similar to the existing results. Sluka KA et. al., Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia, Muscle Nerve. 2001]

Seven or eight days after the second acidic saline injection, the avoidance threshold (0 hour avoidance threshold) for mechanical stimulation was measured, and rats showing an avoidance threshold of less than 4.5 g were used to evaluate the efficacy of the test compound. Vehicle or test compound was intraperitoneally administered at doses of 5, 10 and 20 mg / kg and threshold response response to mechanical stimulation at 30 minutes, 1, 2 and 4 hours was determined.

As can be seen in Table 1 and FIG. 1, mechanical allodynia caused by repeated injections of acidic saline was significantly inhibited upon intraperitoneal administration of test compounds at 5, 10 and 20 mg / kg. In addition, the effect of dose-dependent test compounds was also confirmed by calculating the area under the curve of the foot avoidance response threshold curve over time, and statistically compared to the vehicle group at 10 mg / kg ip and 20 mg / kg ip. It showed a significant effect.

These results indicate that test compounds significantly reduce muscle hyperalgesia in a dose-dependent manner in chronic muscle pain models.

TABLE 1

Avoidance threshold before and after administration of test compound for mechanical allodynia caused by acidic saline injection into the spleen muscles ^a

^a threshold of avoidance response to mechanical stimulation of the right hind paw as measured by the bone filament (g)

^b Baseline was measured before injection of the first acidic saline solution.

^{c The} test compound was tested 7 or 8 days after the second acid saline administration.

^d p <0.05, value for 0 hours by one-way ANOVA and Dunnett test

^e p <0.01, value for 0 hours by one-way ANOVA and Dunnett test

From the above results, it was confirmed that the test compound showed a significant effect in the fibromyalgia disease model.

Claims (32)

1. Prevention of fibromyalgia or associated functional symptoms of fibromyalgia, comprising a therapeutically effective amount of a carbamate compound of Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof Or therapeutic agents:

   [Formula 1]

   

   In Chemical Formula 1,

   R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, C ₁ -C ₈ alkyl, halo-C ₁ -C ₈ alkyl, C ₁ -C ₈ thioalkoxy and C ₁ -C ₈ alkoxy,

   One of A ₁ and A ₂ is CH and the other is N.
2. The agent according to claim 1, wherein R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen and C ₁ -C ₈ alkyl.
3. The agent according to claim 1, wherein the carbamate compound of formula 1 is carbamic acid (R) -1- (2-chlorophenyl) -2-tetrazol-2-yl) ethyl ester of formula (II):

   [Formula 2]

   
4. The method of claim 1, wherein the fibromyalgia is fibromyalitis, fibromyalitis, myocytosis, musculoskeletal pain syndrome, non-articular rheumatoid, pain due to rheumatoid myositis, tension myalgia, hyperalgesia, persistent pain, stiffness And tenderness.
5. The method of claim 1, wherein the associated functional syndromes of fibromyalgia are headache, insomnia, cognitive impairment, depression, temperature abnormalities, irritable bowel syndrome, sicca symptoms, increased sweating, dizziness, tremor, dyspnoea ), Arrhythmias, paraesthesias and chronic fatigue.
6. The pharmaceutical according to any one of claims 1 to 5, which is for mammalian administration.
7. 7. The agent of claim 6, wherein the mammal is a human.
8. The pharmaceutical according to any one of claims 1 to 5, wherein the therapeutically effective amount of the carbamate compound of formula 1 is 50 to 500 mg once daily.
9. The agent according to any one of claims 1 to 5, which is for oral, parenteral, intravenous, intramuscular, subcutaneous or rectal administration.
10. A therapeutically effective amount of a carbamate compound of Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof; And a pharmaceutically acceptable carrier, wherein the pharmaceutical composition for preventing or treating fibromyalgia or associated functional syndrome of fibromyalgia:

    [Formula 1]

    

    In Chemical Formula 1,

    R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, C ₁ -C ₈ alkyl, halo-C ₁ -C ₈ alkyl, C ₁ -C ₈ thioalkoxy and C ₁ -C ₈ alkoxy,

    One of A ₁ and A ₂ is CH and the other is N.
11. The pharmaceutical composition of claim 10, wherein R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen and C ₁ -C ₈ alkyl.
12. The pharmaceutical composition according to claim 10, wherein the carbamate compound of formula 1 is carbamic acid (R) -1- (2-chlorophenyl) -2-tetrazol-2-yl) ethyl ester of formula Composition:

    [Formula 2]

    
13. The method according to claim 10, wherein the fibromyalgia is fibromyalitis, fibromyalitis, myopathy, musculoskeletal pain syndrome, non-articular rheumatoid, pain caused by rheumatoid myositis, tension myalgia, hyperalgesia, persistent pain, stiffness And tenderness.
14. The method of claim 10, wherein the associated functional syndromes of fibromyalgia are headache, insomnia, cognitive impairment, depression, temperature abnormalities, irritable bowel syndrome, sicca symptoms, increased sweating, dizziness, tremor, dyspnoea ), Arrhythmias, paraesthesias, and chronic fatigue.
15. The pharmaceutical composition according to any one of claims 10 to 14, which is for mammalian administration.
16. The pharmaceutical composition of claim 15, wherein the mammal is a human.
17. The pharmaceutical composition according to any one of claims 10 to 14, wherein the therapeutically effective amount of the carbamate compound of formula 1 is 50 to 500 mg once daily.
18. The pharmaceutical composition according to any one of claims 10 to 14, which is for oral, parenteral, intravenous, intramuscular, subcutaneous or rectal administration.
19. Preventing or treating fibromyalgia or associated functional syndrome of fibromyalgia in a subject, comprising administering to the subject a therapeutically effective amount of a carbamate compound of Formula 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof Way:

    [Formula 1]

    

    In Chemical Formula 1,

    R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, C ₁ -C ₈ alkyl, halo-C ₁ -C ₈ alkyl, C ₁ -C ₈ thioalkoxy and C ₁ -C ₈ alkoxy,

    One of A ₁ and A ₂ is CH and the other is N.
20. 20. The method of claim 19, wherein R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen and C ₁ -C ₈ alkyl.
21. 20. The process of claim 19, wherein the carbamate compound of formula 1 is carbamic acid (R) -1- (2-chlorophenyl) -2-tetrazol-2-yl) ethyl ester of formula

    [Formula 2]

    
22. 20. The method of claim 19, wherein the fibromyalgia is fibromyalitis, fibromyalitis, muscular rheumatoid, musculoskeletal pain syndrome, non-articular rheumatoid, pain due to rheumatoid myositis, tension myalgia, hyperalgesia, persistent pain, stiffness. And tenderness.
23. The method according to claim 19, wherein the associated functional syndromes of fibromyalgia are headache, insomnia, cognitive impairment, depression, temperature abnormalities, irritable bowel syndrome, sicca symptoms, increased sweating, dizziness, tremor, dyspnoea ), Arrhythmias, paraesthesias and chronic fatigue.
24. 24. The method of any one of claims 19 to 23, wherein the subject is a mammal.
25. The method of claim 24, wherein the mammal is a human.
26. 24. The method of any one of claims 19 to 23, wherein the therapeutically effective amount of the carbamate compound of Formula 1 is 50 to 500 mg once daily.
27. Use for the prophylaxis or treatment of fibromyalgia or associated functional syndrome of fibromyalgia of a carbamate compound of Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof:

    [Formula 1]

    

    In Chemical Formula 1,

    R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen, C ₁ -C ₈ alkyl, halo-C ₁ -C ₈ alkyl, C ₁ -C ₈ thioalkoxy and C ₁ -C ₈ alkoxy,

    One of A ₁ and A ₂ is CH and the other is N.
28. The use according to claim 27, wherein R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, halogen and C ₁ -C ₈ alkyl.
29. Use according to claim 27, characterized in that the carbamate compound of formula 1 is carbamic acid (R) -1- (2-chlorophenyl) -2-tetrazol-2-yl) ethyl ester of formula

    [Formula 2]

    
30. 28. The method of claim 27, wherein the fibromyalgia is fibromyalitis, fibromyalitis, myeloid rheumatoid, musculoskeletal pain syndrome, non-articular rheumatoid, pain due to rheumatoid myositis, tension myalgia, hyperalgesia, persistent pain, stiffness And tenderness.
31. 28. The method of claim 27, wherein the associated functional syndromes of fibromyalgia are headache, insomnia, cognitive impairment, depression, temperature abnormalities, irritable bowel syndrome, sicca symptoms, increased sweating, dizziness, tremor, dyspnoea ), Arrhythmias, paraesthesias and chronic fatigue.
32. 32. The use according to any one of claims 27 to 31, wherein the carbamate compound of formula 1 is used in an amount of 50 to 500 mg once daily.

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